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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2515-2524
From the Children's Hospital of Orange County, Orange, CA.
We have previously demonstrated a significant inverse correlation
between circulating thrombopoietin (TPO) levels and peripheral platelet
(PLT) counts in patients with thrombocytopenia secondary to
megakaryocytic hypoplasia but not in patients with immune
thrombocytopenic purpura (ITP; Chang et al, Blood 88:3354,
1996). To test the hypothesis that the differences in the circulating
TPO levels in these two types of thrombocytopenia are caused by
differences in the total capacity of Mpl receptor-mediated TPO
clearance, thrombocytopenia was induced in female CD-1 mice either by
sublethal irradiation (irradiated) or rabbit antimouse PLT serum
(RAMPS) for 1 day (1 d RAMPS) and 5 days (5 d RAMPS). A
well-characterized murine model of autoimmune thrombocytopenic purpura,
male (NZW × BXSB) F1 mice (W/B F1), was also
included in this study. All thrombocytopenic mice and their controls
received trace amounts of 125I-recombinant murine TPO
(125I-rmTPO) intravenously and were killed 3 hours postinjection. Blood cell-associated radioactivity was
significantly decreased in all 4 groups of thrombocytopenic mice.
Significantly increased plasma and decreased whole spleen-associated
radioactivity was observed in the irradiated group compared with
controls (P < .05). While a lesser but still significant
increase in plasma and decrease in whole spleen-associated
radioactivity was observed in the 1 d RAMPS mice (P < .05),
there were no significant differences between the 5 d RAMPS nor the W/B
F1 male mice compared with controls, although whole
spleen-associated radioactivity was higher in the W/B F1
male. A significant inverse correlation of plasma and whole spleen-associated radioactivity was demonstrated in W/B F1
male mice (r = This article has been cited by other articles:
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| Copyright © 1999 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
.91, n = 6, P < .05). There was
also a decrease in bone (femur)/blood-associated radioactivity in the
irradiated group compared with controls (P < .05), but a
significant increase in 1 d and 5 d RAMPS mice (P < .01).
Furthermore, the 125I-rmTPO uptake capacity within the
spleen and marrow of immune thrombocytopenic mice appeared to be
associated with a higher megakaryocytic mass when tissue samples were
examined by light microscopy. Internalization of 125I-rmTPO
by megakaryocytes and PLTs in the spleens and marrows of ITP mice was
also demonstrated directly using electron microscopic autoradiography.
Labeled PLTs were also found within splenic macrophages. Additionally,
the mean PLT volumes of RAMPS mice were significantly higher than those
of the control and irradiated mice (P < .05), as was the
bound 125I-rmTPO (cpm) per million PLT (P < .05).
Finally, significantly decreased 125I-rmTPO degradation
products were only found in the plasma of the irradiated mice compared
with control animals (P < .05). These data suggest that the
lack of Mpl+ cells in the mice with thrombocytopenia
secondary to megakaryocytic hypoplasia (irradiated) results in
decreased uptake and degradation of TPO and higher circulating TPO
levels. Furthermore, these data also suggest that, after a brief TPO
surge in response to immune thrombocytopenia (1 d RAMPS), the lack of
an inverse correlation of circulating TPO with PLT counts during
steady-state immune thrombocytopenic mice (5 d RAMPS + W/B
F1 male) is due, at least in part, to its uptake and
degradation by the high PLT turnover and increased mass of megakaryocytes.
